Immune-suppressed organ transplant recipients (OTRs) can develop catastrophic
squamous cell carcinoma (SCC), characterized by multiple primary
tumors, extensive body surface area involvement, or
metastases. There are currently no curative systemic
therapies available. We previously showed that
IL-22 enhances SCC proliferation. Herein, we examined links between
cyclosporine (CSA),
IL-22, and SCC in patients, cell lines, and mice with UV light-induced SCC. Eighteen of 114 OTRs developed catastrophic SCC, which was strongly associated with CSA treatment. We found that CSA drives T cell polarization toward IL-22-producing T22 cells, and CSA treatment increased
IL-22 receptor in SCC cells. SCC tissue from OTRs showed increased expression of IL-22RA1. CSA potentiated rescue by
IL-22 of serum-starved SCC cells; treatment of SCC cells with
IL-22 and CSA increased both their migratory and invasive capacity. In a UV-induced model of SCC in SKH-1 immunocompetent mice, treatment with anti-IL-22 antibody reduced
tumor number and
tumor burden. We found that catastrophic SCC in OTRs is associated with CSA use, which may be acting by favoring T22 polarization. Since anti-IL-22 antibody administration decreased
tumor number and
tumor burden in vivo, blockade of the
IL-22 axis may be developed as a viable therapeutic option for catastrophic SCC.